Glucokinase (sometimes to be abbreviated to as GK in the present specification) (EC2.7.1.1) is one of the four kinds of hexokinases found in mammals, and is also called hexokinase IV. GK is an enzyme that catalyzes the conversion of glucose to glucose-6-phosphate, which is the first step of glycolysis. GK is mainly present in the pancreatic β cell and the liver, and acts in the pancreatic β cell as a sensor of extracellular glucose concentration that defines the glucose-stimulated insulin secretion. In the liver, the enzyme reaction of GK becomes a rate determining factor and regulates glycogen synthesis and glycolysis. The three hexokinases (I, II, III) other than GK reach the maximum enzyme activity at a glucose concentration of 1 mM or below. In contrast, GK shows low affinity for glucose and has a Km value of 8-15 mM which is close to a physiological blood glucose level. Accordingly, GK-mediated promotion of intracellular glucose metabolism occurs, which corresponds to blood glucose changes from normal blood glucose (5 mM) to postprandial hyperglycemia (10-15 mM).
The hypothesis proposed by Matschinsky et al. in 1984 that GK acts as a glucose sensor in the pancreatic β cell and hepatocytes has been demonstrated by the analysis of glucokinase gene manipulation mouse in recent years (see The Journal of Biological Chemistry (J. Biol. Chem.), 1995, vol. 270, page 30253-30256; The Journal of Biological Chemistry (J. Biol. Chem.), 1997, vol. 272, page 22564-22569; The Journal of Biological Chemistry (J. Biol. Chem.), 1997, vol. 272, page 22570-22575; NIHONRINSHO, 2002, vol. 60, page 523-534; and Cell, 1995, vol. 83, page 69-78). That is, GK heterozygous knockout mouse showed a hyperglycemic condition, and further, a disordered glucose-stimulated insulin secretion response. GK homozygous knockout mouse dies shortly after birth with manifestations of marked hyperglycemia and urinary sugar. On the other hand, GK overexpressed mouse (hetero type) showed decreased blood glucose level, increased blood glucose clearance rate, increased liver glycogen content and the like. From these findings, it has been clarified that GK plays an important role in the systemic glucose homeostasis. In other words, decreased GK activity causes insulin secretion failure and lower liver glucose metabolism, which develops impaired glucose tolerance and diabetes. Conversely, GK activation or increased GK activity due to overexpression causes promoted insulin secretion and promoted liver glucose metabolism, which in turn increases the systemic use of glucose to improve glucose tolerance.
In addition, it has been clarified from the analysis of a report on GK gene abnormality mainly in the family of MODY2 (Maturity Onset Diabetes of the Young) that GK also acts as a glucose sensor in human, and plays a key role in glucose homeostasis (see Nature, 1992, vol. 356, page 721-722). In GK gene abnormality, due to the decreased affinity of GK for glucose (increased Km value) and decreased Vmax, the blood glucose threshold value of insulin secretion increases and the insulin secretory capacity decreases. In the liver, due to the decreased GK activity, decreased glucose uptake, promoted gluconeogenesis, decreased glycogen synthesis and liver insulin resistance are observed. On the other hand, a family with a mutation increasing the GK activity has also been found. In such family, fasting hypoglycemia associated with increased plasma insulin concentration is observed (see New England Journal Medicine, 1998, vol. 338, page 226-230).
As mentioned above, GK acts as a glucose sensor in mammals including human, and plays an important role in blood glucose regulation. On the other hand, control of blood glucose utilizing the glucose sensor system of GK is considered to open a new way to treat diabetes in many type 2 diabetes patients. Particularly, since a GK activating substance is expected to show insulin secretagogue action in the pancreatic β cell and glucose uptake promotion and glucose release suppressive action in the liver, it will be useful as a prophylactic or therapeutic drug for type 2 diabetes.
In recent years, it has been clarified that pancreatic β cell type glucokinase expresses locally in the feeding center (Ventromedial Hypothalamus: VMH) of rat brain. A subset of nerve cell present in VMH is called glucose responsive neuron, and plays an important role in the body weight control. From electrophysiological experiments, the neuron is activated in response to physiological changes in the glucose concentration (5-20 mM). However, since the glucose concentration sensor system of VHM is assumed to have a mechanism mediated by glucokinase as in the case of insulin secretion in the pancreatic β cell, separately from pancreatic β cell and the liver, a pharmaceutical agent capable of activating glucokinase of VHM has a possibility of providing not only a blood glucose corrective effect but also improvement of obesity.
As mentioned above, a pharmaceutical agent capable of activating GK is useful as a prophylactic or therapeutic drug for diabetes and chronic diabetic complications such as retinopathy, nephropathy, neuropathy, ischemic cardiac diseases, arteriosclerosis and the like, and further, as a prophylactic or therapeutic drug for obesity.
As the indole compound, the following compound has been reported.
(1) It has been reported that a compound represented by the formula:
whereinring A is an optionally substituted monocyclic or bicyclic aromatic ring;ring B is an optionally substituted 6-membered unsaturated hydrocarbon ring or an optionally substituted 6-membered unsaturated heterocycle containing one nitrogen atom;ring C is an optionally substituted 5-membered heterocycle containing one or two nitrogen atoms;W is a single bond or —CH═CH—;X is —N(R1)— or an oxygen atom;Y is a carbon atom or a nitrogen atom;Z is —N(R2)— or a nitrogen atom; andR1 and R2 are the same or different and each is a hydrogen atom or a lower alkyl group,is useful as an antitumor agent or an angiogenesis inhibitor (see WO 95/07276 and JP-A-2000-309534).(2) It has been reported that a compound represented by the formula:
whereinX: NR33 (R33: a C1-8 alkyl group, a C1-8 alkenyl group or a C1-8 alkynyl group), NH, O or S; andR2: a hydrogen atom, a C1-8 alkyl group, a C1-8 halo alkyl group or (CH2)nS(═O)2R11 (n: 0 to 8; R11: an optionally substituted C5-14 aryl group or an optionally substituted C3-11 hetero aryl group),is a PPAR-γ binder, and useful for diabetes (see JP-A-2004-529855).(3) It has been reported that a compound represented by the formula:
whereinR2; a hydrogen atom, an optionally substituted C1-10 alkyl group, N(R4)2 or OR4 (R4; a hydrogen atom, a C1-6 alkyl group, a C3-10 cycloalkyl group, an aryl group, a heterocyclic group, CF3, a C2-6 alkenyl group or a C2-6 alkynyl group),is an anticancer agent, an Akt inhibitor or a tyrosine kinase inhibitor (see US-B-2004/0102360 and WO 2004/014851).(4) It has been reported that a compound represented by the formula:
whereinR1: a hydrogen atom, an alkyl group, a cycloalkyl group, an aromatic group and the like; andR2: a hydrogen atom, an alkyl group and the like, is a Na+/H+ exchanger inhibitor (see EP 622356 B).(5) It has been reported that a compound represented by the formula:
whereinQ: a bond, CO, SO2, a C1-6 alkylene group and the like; andR0: an optionally substituted monocyclic or bicyclic 5- to 14-membered aryl group, or an optionally substituted monocyclic or bicyclic 5- to 14-membered heteroaryl group, is a FXa inhibitor (see EP 1314733 B).(6) It has been reported that a compound represented by the formula:
whereinW: O or S;R: a hydrogen atom or an alkyl group;X1 and X2: an optionally substituted arylene group or an optionally substituted heteroarylene group;
whereinR3, R4, R20 and R21: a hydrogen atom or an alkyl group; and R1, R2, R5 and R22
wherein R8, R9R10, R11 and R12: a hydrogen atom, an alkyl group and the like; andR24: an alkyl group etc.,is an antibacterial agent or a HIV inhibitor (see US-A-2004/0063645).(7) It has been reported that a compound represented by the formula:
whereinX: O, S or NR23 (R23: a hydrogen atom, an optionally substituted alkyl group, an optionally substituted heteroalkyl group or an acyl group);R4 and R5: a hydrogen atom, an optionally substituted alkyl group, an optionally substituted heteroaryl group, COR15 (R15: a hydrogen atom, an optionally substituted alkyl group etc.) and the like; andE and G are bonded to form an optionally substituted aryl, an optionally substituted heteroaryl and the like, is an anticancer agent (see WO 02/096910).(8) It has been reported that a compound represented by the formula:
whereinAr1: an optionally substituted carbon ring;Y: CRpRv (RP and RV: a hydrogen atom, a C1-5 alkyl group etc.), O, S(O)n (n: 0, 1, 2), N—Rx (Rx: a hydrogen atom, a C1-5 alkyl group etc.) and the like; andQ: N or CRpRv,has a cytokine inhibitory activity, and is useful as an anti-inflammatory agent (see WO 03/087085).(9) It has been reported that a compound represented by the formula:
whereinR1: a halogen atom, a nitro group and the like;R2: a C2-5 alkyl group or —CH2—R4 (R4: a C3-6 cycloalkyl group);R3: an optionally substituted 5- or 6-membered aromatic heterocyclic group,is a GK activator, and useful for diabetes and the like (see WO 04/031179).(10) A compound represented by formula:
(see Youji Huaxue 1983, vol. 128, page 129-130) has been reported.
However, any references do not disclose that a compound represented by the following formula (I) has glucokinase activating action, or a compound represented by the following formula (II).